Vascular heparan sulfate proteoglycan (HSPG) plays an important structural and functional role in the vascular permeability barrier. HSPG is comprised of two major components: heparan sulfate (HS) (a glycosaminoglycan (GAG)), and a protein core. In animal models, antibodies to HSPG protein core cause vascular injury. In humans and in animal models of systemic lupus erythematosus (SLE), investigators have demonstrated serum antibodies and deposited antibodies in glomeruli which are broadly cross-reactive with both DNA and HS GAG. In humans, we demonstrated autoantibodies to intact HSPG. We further demonstrated immunospecific autoantibodies to HS GAG in patients with vascular disease. Preliminary data from our laboratory also indicate the presence of autoantibodies to HSPG protein core in human SLE sera. The hypothesis of this proposal is that autoimmunity to vascular HSPG causes vascular injury in autoimmune disease. Our hypothesis has significance for understanding the specificity and significance of polyspecific autoantibodies reactive with anionic molecules in autoimmune disease. The pathologic origin and significance of anti-DNA and anti- phospholipid antibodies in autoimmune disease is unknown. We propose that HS is the immunospecific epitope of high affinity with which anti-DNA and anti-phospholipid antibodies are reactive. High affinity autoantibodies to HS are pathologically significant because they are more efficient than broadly cross-reactive, low affinity autoantibodies in activating complement, and initiating inflammation. PG protein core epitopes also play a role in organ-specificity. A corollary hypothesis proposes that organ-specific (vascular-specific) HSPG protein core epitopes are immunologic targets in organ-specific autoimmune disease. Careful immunochemical studies are required to investigate this hypothesis. Hybridoma technology will be employed to study the immunochemistry of monoclonal anti-HSPG autoantibodies from humans and mice with autoimmune vascular disease. We will also determine this immunodominant sites of HSPG protein core recognized by murine SLE T cell clones. Finally, we will explore mechanisms of autoimmune vascular injury by investigations of complement activation and endothelial cell cytotoxicity employing monoclonal autoantibodies to HSPG from patients and mice with autoimmune vascular disease.